Enhanced brain delivery of oleanolic acid by GSH-PEGylated liposomes and its amelioration of scopolamine-induced cognitive dysfunction via multi-target regulation.

Oleanolic acid (OA) exhibits pronounced neuroprotective effects in the central nervous system; however, its clinical translation is limited by poor solubility and low bioavailability. To overcome these limitations, we developed glutathione-PEGylated OA liposomes (GSH-PEG-OA-LIP) via a post-insertion method, achieving an load efficiency of 94.2%. In vivo imaging demonstrated that GSH-PEG modification significantly prolonged blood circulation and enhanced brain accumulation compared to unmodified liposomes. In a mouse model of scopolamine (SCOP)-induced cognitive deficit, GSH-PEG-OA-LIP treatment effectively reversed short- and long-term memory impairments. Biochemical analyses revealed that the treatment restored hippocampal cholinergic function by increasing acetylcholine (ACh) levels and choline acetyltransferase (ChAT) activity, while simultaneously alleviating oxidative stress through reduced malondialdehyde (MDA) content and increased superoxide dismutase (SOD) activity. Furthermore, molecular docking and molecular dynamics simulations confirmed stable interactions between OA and key signaling targets-specifically PKC, PI3Kγ, MEK, and IP3R-suggesting a multi-targeted mechanism of action. Collectively, these results highlight GSH-PEG-OA-LIP as an efficient brain-targeted delivery system and a promising therapeutic strategy for cognitive disorders.